Cardiovascular Physiology Concepts
                                    Richard E. Klabunde, Ph.D.


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Click here for information on Cardiovascular Physiology Concepts, published by Lippincott Williams & Wilkins (2005)


 


 

Vascular Signal Transduction Mechanisms (G-Protein, IP3 and cGMP Linked)

 

There are several signal transduction mechanisms that modulate intracellular calcium concentration and therefore the state of vascular tone.  Three different mechanisms will be described here: 1) Gs-protein-coupled pathway, 2) phosphatidylinositol pathway, and 3) nitric oxide-cGMP pathway.  

Gs-Protein  Coupled Signal Transduction

Like heart muscle, the Gs-protein coupled pathway in smooth stimulates stimulates adenylyl cyclase (AC), which catalyzes the formation of cAMP.  Unlike the heart, however, an increase in cAMP in vascular smooth muscle causes reduced contraction (i.e., relaxation). Myosin light chain kinase (MLCK) phosphorylates myosin and causes contraction; however, MLCK is inhibited by cAMP.  

The Gs-protein is coupled to several important receptors that bind vasodilator substances, among which are b2-adrenoceptors (bind to b2-agonists such as epinephrine and isoproterenol), A2 purinergic receptors (bind to adenosine), and IP receptors (bind prostacyclin, PGI2).

IP3- Coupled Signal Transduction

The phosphatidylinositol pathway in vascular smooth muscle is similar to that found in the heart Alpha-agonists (e.g., norepinephrine) acting via a1-adrenoceptors, angiotensin II (AII) acting via AT1 receptors, endothelin-1 (ET-1) acting through ETA receptors, vasopressin acting via V1 receptors, and acetylcholine acting through M3 receptors activate phospholipase C (PL-C) causing the formation of inositol triphosphate (IP3) from phosphatidylinositol (PIP2).  The IP3 then stimulates the sarcoplasmic reticulum (SR) to release calcium. The formation of diacylglycerol (DAG) activates protein kinase C (PK-C), which can also contribute to vascular smooth muscle contraction via protein phosphorylation.

cGMP-Coupled Signal Transduction

A third mechanism that is very important in regulating vascular smooth muscle tone is the nitric oxide (NO)-cGMP system. Vascular endothelial cells normally produce NO, which diffuses from the endothelial cell to adjacent smooth muscle cells where it activates guanylyl cyclase leading to increased formation of cGMP and vasodilation. The precise mechanisms by which cGMP relaxes vascular smooth muscle is unclear; however, cGMP can activate a cGMP-dependent protein kinase, inhibit calcium entry into the vascular smooth muscle, activate K+ channels, and decrease IP3.

Acetylcholine (ACh), whether released by cholinergic autonomic nerves or exogenously administered, binds to muscarinic receptors on the vascular endothelium (M3 receptors in coronary vessels), which stimulates the formation and release of NO as described above to produce vasodilation. Certain antihypertensive and antianginal drugs are called nitrodilators because they release NO, and thereby mimic the effect of endothelial produced NO.

RK Revised 02/02/2008

 


DISCLAIMER: These materials are for educational purposes only, and are not a source of medical decision-making advice.

© 1999-2008 Richard E. Klabunde, all rights reserved.